The long range goal of this project is to understand the roles of the brain leptin receptor (Lepr) isoforms in leptin signaling. Two dominant Lepr isoforms have been identified: one with a long cytosolic domain (Lepr-Rb) present at high levels in the hypothalamus and postulated to be the primary signaling isoform, and one with a short cytosolic domain (Lepr-Ra) which is ubiquitously expressed. The db/db mouse expressed only the sort isoforms, and current hypotheses predict that replacing the Lepr-Rb isoform in the central nervous system of db/db mice will correct the obesity in these mutants. It is unknown, however, if expression of Lepr-Rb exclusively within the central nervous system and in the absent other Lepr isoforms centrally and peripherally produces normal leptin signaling. This proposal addresses this question through the study of transgenic (Tg) animals expressing neuronally restricted Lepr-Rb alone (Tg db3j/db3j) or with the native Lepr-Ra (Tg db/db). Metabolic parameters and expression of neuropeptides and proteins which are dysregulated in ob/ob or db/db mice, as well as measures of food intake and body weight, will be examined in these animals. These experiments will provide a more complete description of the roles that leptin receptor isoforms play in leptin signaling.